Unit system having multiplicity of means for dispensing useful agent

ABSTRACT

A system is disclosed for dispensing an useful agent. The system comprises (1) means for storing an agent, (2) an agent stored in the means, (3) means for releasing agent from the system, (4) means for absorbing fluid into the system surrounding the storing means, and (5) means for admitting fluid into the system. In operation fluid is admitted into the system by the admitting means cooperating with the absorbing means, causing it to increase in dimensions and apply force against the storing means, which force urges the storing means to decrease its dimensions and correspondingly dispense agent through the releasing means from the system. Laminates are disclosed useful for manufacturing the system.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. Patent ApplicationSer. No. 020,521 filed on Mar. 14, 1979, and now abandoned whichapplication is a division of U.S. Patent Application Ser. No. 862,363filed on Dec. 20, 1977 and now abandoned, and benefits is claimed oftheir filing dates. This application and Ser. No. 020,521 and 862,363are all assigned to the Alza Corporation of Palo Alto, Calif.

FIELD OF THE INVENTION

This invention pertains to a self-powered system for delivering abeneficial agent to an environment of use.

THE PRIOR ART

Commercially important, manufactured devices useful for dispensingbeneficial agent to an environment of use are known to the prior art.For example, U.S. Pat. No. 3,760,984 issued to patentee Theeuwesdiscloses a device comprising an inner chamber formed of a heatshrinkable polymer carrying on its outer surface an osmotic solute and adistant layer of a polymer permeable to fluid. The device has a meansfor filling the chamber. In U.S. Pat. No. 3,865,108, Hartop discloses adevice consisting of a base with a hollow that holds a receptable. Thedevice can have a highly flexible, water permeable skin that assures thedevice will not break apart in contact with fluid. A drug is releasedfrom the receptacle by cutting it. Neither the skin nor the severedreceptacle are disclosed as having rate controlling properties forgoverning the rate of release from the device. In U.S. Pat. No.3,987,790, Eckenhoff et al disclose an improvement in osmotic devicesconsisting of a conduit for filling the devices. In U.S. Pat. No.3,971,376, Wichterle claims a device consisting of a capsule havingunitary walls formed of a substantially non-collapsable material that isexposed to the environment of use. A textile fabric is imbedded in thematerial for imparting strength and minimizing problems due to poormechanical properties of the material that occur during fluid uptake. InU.S. Pat. No. 3,995,631, Higuchi et al, disclose a bag bearing on itsouter surface a layer of an inorganic solute, and a distant wall formedof a material having part controlled permability to fluid.

While the devices above described are useful for dispensing numerousagents to many environments of use, and while the devices represent amajor advancement in the delivery arts, there are instances where aninventively novel, different and useful device also would enjoy wideapplication. For example, when the device must be placed in anenvironment of use where a need exists for controlling the amount ofagent discharged from the device, a device having a means forinteracting with imbibed fluid and swelling to some preselectedequilibrium state, thereby producing a force that can be used fordriving a known amount of agent from the device, would enjoy immediateacceptance, and also be a valuable contribution in the fields ofcommerce and science.

OBJECTS OF THE INVENTION

Accordingly, it is an immediate objects of this invention to provide anovel and useful dispensing system for dispensing of an agent to producea beneficial effect, which system overcomes the aforesaid disadvantagesassociated with the prior art.

Still another object of the invention is to provide a new dispensingsystem which system can dispense an agent at a controlled rate for aprolonged period of time in an environment of use having a limitedamount of fluid available for use by the system.

Yet another object of the invention is to provide a dispensing systemhaving a means for absorbing fluid and retaining a significant fractionof the fluid within the means as a source of power useful for dispensingan agent from the system.

Still another object of the invention is to provide a system havingmeans for admitting fluid into the system at a controlled rate, meansfor absorbing the admitted fluid and exhibiting the ability to increasein dimensions over time, which increase can be used as a mechanical,driving power for dispensing agent from the system.

Yet another object of the invention is to provide a dispensing systemwhich system is self-powered, easy to manufacture, and can be used fordispensing beneficial agents to animals including humans, and into otherbilogical and nonbiological environments of use.

Another object of the invention is to provide a dispensing system thatis empty until filled, and when filled can administer a completepharmaceutical dosage regimen for a period of time, the use of whichrequires intervention only for initiation and termination of theregimen.

An additional object of the invention is to provide a laminate usefulfor fabricating dispensing systems, which systems can function in aplurality of fluid environments.

It is a further object of the invention to provide a novel therapeuticsystem manufactured as a drug delivery device, which can operate toyield results substantially equivalent to those obtained with asustained release method of drug administration.

Other objects, features and advantages of the invention will be apparentto those skilled in the art, from the detailed description of thisspecification, taken in conjunction with the drawings, and theaccompanying claims.

SUMMARY OF THE INVENTION

The invention concerns a system for dispensing an agent to anenvironment of use. The system is manufactured as a dispensing deviceespecially designed for dispensing drug to a biological environment. Thesystem comprises an intermediate, expandable fluid absorbing means madeof a hydrophilic material surrounding at least partially an innercollapsible storing means made of an elastomeric material, whichcontains the agent. The intermediate means is surrounded by a wallformed of a rate controlling material that admits fluid into the system.In operation, the system releases agent in response to the intermediatemeans absorbing the admitted fluid and expanding, thereby exertingpressure on the inner means which collapses and ejects agent from thesystem. The invention also concerns a laminate comprising the wall andthe inner positioned means.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not drawn to scale, but are set forth toillustrate various embodiments of the invention, the figures are asfollows:

FIG. 1 is a front, elevational view illustrating a device made accordingto the invention, which depicts a storing means and the fluid admittingmeans;

FIG. 2, taken in conjunction with FIG. 1, illustrates the device inopened-section along 2a-2a and 2b--2b, for illustrating the structure ofthe device; and

FIGS. 3a and 3b illustrate the laminate defining the structural membersof the device, taken through 3--3 of FIG. 2.

In the drawings and specification, like parts in related Figures areidentified by like numbers. The terms appearing ealier in thespecification, an in the description of the drawings, as well asembodiments thereof, are further described elsewhere in the disclosure.

DETAILED DESCRIPTION OF THE DRAWINGS

Turning now to the drawings in detail, which are an example of a new anduseful device for dispensing an agent, including drug, and which exampleis not to be construed as limiting, one device is illustrated in FIG. 1by the number 10. In FIG. 1, device 10 comprises means 11 for admittingfluid into device 10. Means 11 is a wall or housing, also indentifiableas 11, that is shaped, sized and adapted for placing device 10 in thepreselected environment of use. Wall 11 surrounds and defines aninternal space 11a designed for receiving and housing means 13. Wall 11is made from a material that controls the amount of an exterior fluidpresent in the environment of use that can enter device 10. The materialforming wall 11, in addition to governing the volume of fluid admittedinto device 10, also imparts physical integrity and structure to device10 throughout the dispensing period. Means 13, seen in dashed lines inFIG. 1, is designed for storing an active agent, not shown, which agentin a presently preferred embodiment is a drug. Means 13 is manufacturedas a container, also identified as 13 and seen as dashed lines inFIG. 1. Container 13 has a lead end 15 that forms and defines means 14for releasing agent from container 13 to the exterior of device 10.Container 13 is made from a material that can house a beneficial agentsubstantially free from any adverse effects on the agent. The containeralso can house the agent over a prolonged period of time sheltered fromany possible adverse actions present in the environment of use. Means14, which is preferrably formed during the manufacture of container 13,can also be described as a passageway, and it has internal dimensionspreselected for assisting in governing the rate of release of agent fromdevice 10. Container 13 has a trailing end 16 and an exterior surfacesurrounded in whole or in at least a part by means 12. Container 13 ismade of an elastomeric, or other low-modulus material, that can decreaseits dimensions over time, and more particularly, collapse in response topressure applied against the exterior surface of container 13. FIG. 1also illustrates means 12, seen in dashed lines, and in spaced relationwith wall 11 and container 12.

Means 12, as seen in housing 11a, is positioned between the insidesurface of wall 11 and the exterior surface of container 13. Means 12 ismade of a hydrophilic, swellable material, designed for absorbing andreversibly retaining fluid. This physical-chemical property causes 12 toincrease its space occupying dimensions, which action is transmitted asan applied force against container 13. This force correspondinglydiminishes the dimensions of container 13 and urges the container todispense agent from the device. The increase in dimensions of theswellable material occurs in cooperation with (1) wall 11 that regulatesthe volume of fluid admitted and available in the device, with (2)container 13 that collapses in response thereto, and with (3) thepassageway that assists in governing release from the device. Thestructural members of the device act as a unit system to achieve thedesired result.

FIG. 2 illustrates device 10 of FIG. 1 in opened-section seen incross-section along lines 2a-2a and 2b--2b of FIG. 1. FIG. 2 depicts theintegral structure of device 10 comprising wall 11, an outer laminaforming the housing of device 10, which lamina has a surface, that facesthe environment of use when device 10 is placed therein, aand an innersurface faced in laminar arrangement with means 12. Means 12, describedabove, and it is the structural equivalent of an intermediate laminahving a surface faced towards lamina 11 and surface faced towards thewall of container 13. The outer surface of the wall of container 13 isessentially in laminar arrangement with the intermediate and outermembers forming device 10.

FIG. 3a and 3b illustrate views taken through 3--3 of FIG. 2. FIG. 3shows a superposed laminar arrangement comprising lamina 11 formed of amaterial that regulate the passage of fluid and which material maintainsits physical and chemical integrity throughout the dispensing periodpositioned adjacent to lamina 12. Lamina 12 is formed of a swellable,hydrophilic polymer that can imbibe and reversibly retain aqueous andbiological fluids positioned adjacent to the wall of container 13. Thewall of container 13 is the functional equivalent of a lamina, and 13 isformed of an elastomeric material that collapses in operation to producethe intended results. FIG. 3b shows a novel laminate provided by theinvention comprising laminae 11 and 12.

While FIGS. 1 through 3 are illustrative of various systems that can bemade according to the invention, it is to be understood these systemsare not to be construed as limiting, as they can take a wide variety ofshapes, sizes and forms adapted for delivering an agent including drugto many and varied different environments of use. For example, system 10can be manufactured for dispensing drug to animals, which term includeswarm-blooded mammals, humans, household, farm, sport and zoo animals.The devices can also be used for dispensing drugs to avians, fishes andreptiles. Dispensing device 10 can be sized, shaped and adapted fordispensing drug to body cavities and body openings, and for usesincluding oral administration, intramuscular implants, intrauterine,vaginal, cervical, rectal, nasal, ear, and dermal applications. Device10 also can be used as an artificial gland, and for arterial and venousadministration of drug. The device can be made for use in homes,hospitals, nursing homes, clinics, ships, laboratories, factories andthe like.

DETAILED DESCRIPTION OF THE INVENTION

Device 10, as used for the purpose of the invention, consists of a wall11, or housing, made of a substantially polymeric material. Thismaterial, is preferrably rigid, and it permits pressure to be exertedagainst it without any major change in its shape or dimensions, therebyassuring that pressure generated in device 10 is exerted againstcontainer 13. Housing 11 is made from a semipermeable polymer thatregulates the passage of fluid into the device. The semipermeablepolymers suitable for forming the wall are polymers that displayselective water permeability. The phrase selective water permeability,as used herein, denotes polymers that are permeable to the passage ofwater and essentially impermeable to the passage of solute. Thesemipermeable polymers act in cooperation with the hydrophilic hydrogelsin the device and govern the passage of water through the wall into thedevice. Generally, the semipermeable polymer will have a waterpermeability pf 0.01 to 10 cc/cm² /hr or/day or longer. Typicalsemipermeable polymers suitable for forming the wall include celluloseacylate, cellulose diacylate, cellulose triacylate, cellulose acetate,cellulose diacetate, cellulose triacetate, cellulose polymes having atleast one acyl group with the remaining degrees of substitution on theanhydroglucose units selected from hydrogen, hydroxal and hydrocarbyl.The volume of water that passes through the wall can be furthercontrolled by selecting cellulose polymers possessing a high degree ofsubstitution, for example, the polymer has undergone esterification oresterification, particularly acylation towards completition, bydecreasing or increasing the size of substituting groups on thecellulose polymer, and by selecting hydrophobic and hydrophilic groupsas substitutients on the polymer forming wall 12. Additional watersemipermeable polymers that can be used include polymeric epoxides,semipermeable membranes made from copolymers of an alkylene oxide andalkyl glycidyl ether, semipermeable polyurethanes, polyamides,polyacrylic esters, membranes of ionically associated polyelectrolytes,polymers formed by the coprecipitation of a polycation and a polyanion,semipermeable derivatives of polystyrene such as poly(sodiumstyrenesulfonate) and poly(vinlbenzyltrimethlammonium chloride),polyaromatics, and the like. Semipermeable polymers are disclosed inU.S. Pat. Nos. 3,133,132; 3,173,876; 3,276,586; 3,541,005; 3,543,142;and 3,845,770.

Wall 11 also can be made from a microporous polymeric material whosepore size regulates the volume of fluid that enters the device.Representative microporous polymers have a pore size of up to severalhundred microns, down to several angstroms or smaller. Typicalmicroporous polymers include microporous polyesters, polycarbonates,microporous polyamides, polyvinyl chloride with a pore size of about 5Aor less to 150 microns, microporous polyamides, polyimides,polybenzimidazoles, acetal polymers, phenolic polesters, and the like.Procedures for preparing microporous polymers are described in SyntheticPolymer Membranes by R. E. Kesting, Chapters 4 and 5, 1971, published byMcGraw Hill, Inc.; in Chemical Reviews, Vol. 18 pages 373 to 455; 1934;Polymer Eng. and Sci., Vol. 11, pages 811 to 829, 1971; and in U.S. Pat.Nos. 3,565,259; 3,615,024; 3,751,536; 3,801,692; 3,852,244; 3,849,528;and 4,160,452.

Wall 11, in an inventive embodiment, also can be made from a microporouspolymer whose pores are filled with a water permeable material thatregulates the passage of water into the device. Generally, themicroporous polymer has from 5 to 50% pores interconnected throughtortuous paths which extend from one surface of the wall to the othersurface of the wall. Generally, polymers having a pore size of from 10angstroms to 10 microns can be used for manufacturing the device. Themicroporous polymers can embrace structures characteristic ofmicroporous polyolefins, polyamides, polycarbonates, polyesters,polysytrenes, polysulphones, polyimides, polyvinyls, polyarylenes,polyaldehydes, polyarylates, polyhaloolefins, polyacetals,polyacrylates, polyurethanes, the homopolymers and copolymers thereof,and the like.

The pores of the polymer can be filled with a hydrophilic, or ahydrophobic material that exhibits selective permeability to the passageof water. Representative materials include glycerin, ethylene glycol,propylene glycol, methyl cellulose mixed with water, mixtures ofpropylene glycol monostearate and oils, gum tragacanth, polyoxyethylenestearate, alkylene diols wherein the alkylene has 2 to 10 carbons suchas poly(1,5)-pentanediol, polyesters of alkylene glycols and a monobasicor dibasic acid such as ethylene glycol diacetate, and the like.

The material can be added to the pores by immersion of a microporouspolymeric film in a bath containing the material to let it fill themicropores. The material can be added to the polymer during casting ofthe polymer. For example, pulverized solid, cross-linkedpolymethylmethacrylate, an insoluble swellable polymer that allows forthe presence of water, is added to a polymer dissolved in a solvent,such as ethylene vinyl acetate copolymer in methylene chloride, with thecopolymer cast and the solvent evaporated to leave a film that functionwith microporous characteristics. The micropores of a polymeric film,for example a film of polyhexamethylene adipamide, can be charged byspreading and working into the pores hydroxyethyl methacrylate-ethyleneglycol dimethacrylate dissolved in diacetine, followed by evaporationand wiping the film clean. The micropores also can be filled with ahydrogel cross-linked in the pores. For example, the hydrogel canconsist of a sparingly cross-linked copolymer of a monoester of anolefinic acid and a polyfunctional alcohol having an esterifiablehydroxyl group and at least one additional hydrophilic functional group,with a diester of an olefinic acid and an alcohol having at least twoesterifiable hydroxyl groups. Examplary olefinic acids include acrylicand methacrylic acids, and exemplary alcohols include polyalkyleneglycol, trialkanolamine, polyvinyl alcohol, and the like. The microporesof a polymer for example polyvinyl chloride can be filled with ahydrogel by copolymerizing a glycol and a mono or di(meth)acrylate in asolvent in the pores, followed by irradiating with x or gamma rays. Themicropores of a polymer also can be filled with the hydrophilic polymersdisclosed later in the specification. Generally, the microporous wallwill have a thickness, depending on the device and its use, of fromabout 0.01 mm to 7 mm, or more.

Representative of swellable, hydrophilic polymers, suitable for formingmeans 12, are for example, hydrogels, lightly cross-linked,predominately linear polymers, but also including hydrophilic polymershaving dimensional networks, such cross-links formed in both structuresby covalent or ionic bonds. These polymers interact and absorbbiological and aqueous fluids and swell or expand to some equilibriumstate. The polymers swell to a very high degree without dissolution,usually exhibiting a 5 to 50 fold volume increase. In an embodiment, theinvention provides devices using hydrogels that can be cross-linked to apreselected density, which makes it possible to control the volumeincrease of the hydrogel to some equilibrium value. This increasedvolume can be equal to or greater than the volume of the filledcontainer, thereby assuring complete discharge of agent from thecontainer. The swellable hydrophilic polymers suitable for the presentapplications include poly(hydroxyalkyl methacrylates); poly(acrylamide);poly(methacrylamide) and derivatives; poly(N-vinyl-2-pyrrolidone);anionic and cationic hydrogels; poly(electrolyte) complexes;cross-linked protein polymers; poly(vinyl alcohol) having a low acetateresidual and cross-linked with glyoxal, formaldehyde or glutaraldehyde;poly(saccharide); methylcellulose cross-linked with a dialdehyde; amixture of agar and sodium carboxymethylcellulose; swellable starch; awater-insoluble, water swellable copolymer produced by forming adispersion of finely divided copolymer of maleic anhydride with styrene,ethylene, butylene or isobutylene cross-linked with from 0.001 to about0.5 mole of a polyunsturated cross-linked agent per mole of maleicanhydride in the copolymer as disclosed in U.S. Pat. No. 3,989,589;water-swellable, lightly cross-linked hydrogels made of cross-linkedpolymers of N-vinyl lactams and alkyl lactams made according toprocedures in U.S. Pat. Nos. 3,532,679 and 3,992,562; and the like.Generally, lamina 12 will have a thickness of about 0.001 mm to 7 mm,and in a presently preferred operative embodiment, it will have anexpanded or swelled thickness state approximately equal to the internaldiameter of container 13, for producing a complete collapse of container13 and discharge of agent from device 10.

Representative of materials suitable for manufacturing container 13 arematerials that can be designed into a shaped container, structured as anelastomeric tube or capsule, which collapses in response to externallyapplied pressure, thereby dispensing agent or drug. Typical elastomericpolymers include natural rubber, often identified by the synonymspoly(2-methyl-1,3-butadiene) and cis-1,4-polyisoprene, gutta percha ortrans-polyisoprene, cyclized rubber, silicone rubber, synthetic isoprenerubber, butadiene rubber, copolymeric styrene-butadiene rubbers, nitrilerubber, chloroprene rubber, ethylene-propylene rubbers, butyl rubbers,and the like. These elastomric materials are disclosed in Handbook ofCommon Polymers, by Scott and Roff, Sections 29 through 40, 1971,published by the Chemical Rubber Co., Cleveland, Ohio. Container 13,formed of the above representative materials, can have a wall of varyingthickness, usually about 0.001 mm to 7 mm, or more depending on thecontainer and the use of device 10. Container 13 is manufactured with apassageway for dispensing agent or drug, and it can be made to form apassageway when device 10 is in the environment of use. Passageway 14will have a cross-section of 1 to 20 mils. When passageway 14 is formedin the environment of use, it is closed with a water-soluble plug of anerodible material, such as noncross-linked poly(vinyl alcohol), gelatinor the like that erodes to form the passageway. The end of container 13including passageway 14 can also receive a tube or conduit, not shown,for transporting agent dispensed from the device to a receiving sitelocated away from the device.

Exemplary useful or active agents that can be administered according tothe spirit of the invention include agents that benefit the environment,manufacture and science. The term agent includes algicides,anti-oxidants, air purifiers, biocides, bactericides, catalysts,chemical reactants, cosmetics, disinfectants, drugs, fungicides,flavoring agents, foods, food supplements, fertility inhibitors,fermentation agents, fertility promoters, germicides, insecticide,microorganism alternators, nutrients, pesticides, plant growthpromoters, plant growth inhibitors, preservating agents, slimicides,surfactants, sterilization agents, sex sterilants, vitamins, and otherlike agents that benefit animals and man.

Exemplary drugs that can be administered according to the spirit of theinvention include locally and systemically acting drugs. These drugsinclude a member selected from the group consisting of physiologicallyand pharmacolgically acting drugs such as gastrointestinal administrabledrugs, central nervous system acting drugs, hypnotic, sedative, psychicenergizer, tranquilizer, anticonvulsant, anti-parkinson, musclerelaxant, analgesic, antipyretic, anti-inflammatory, anesthetic,antispasmodic, antimicrobial, antiviral, antiulcer, hormonal,sympathomimetic, diuretic, hypoglycemic, vitamins, contraceptive, andopthalmic drugs. These beneficial drugs and their does amounts forhumans are known to the art in Drills' Pharmacology in Medicine, editedby DiPalma, Joseph R., 1965, published by McGraw-Hill Book Company, NewYork, in Pharmacological Basis of Therapeutics, by Goodman and Gilman,4th Edition, 1970, published by MacMillian Co., London, and in U.S. Pat.No. 3,977,404, which patent is assigned to the ALZA Corporation of PaloAlto, Calif., the assignee of this application. The drug in thecontainer can be mixed with a pharmaceutically acceptable liquid such aswater, saline, cottonseed oil, sesame oil, ethylene oleate, isopropylmyristate, propylene glycol, and the like. The drug can be present insolution, in semi-solid or paste formulation, in a thixotropic state andthe like, which form permits controlled dispensing of drug from thedevice. Pharmaceutically acceptable carriers and the like are known tothe art in Remington's Pharmaceutical Science, 14th Edition, pages 1461to 1762, 1970, published by the Mack Publishing Company, Easton,Pennsylvania.

The following examples are illustrative of the present invention, andthey should not be considered as limiting the scope of the invention inany way, as these examples and other equivalents thereof will becomemore apparent to those versed in the art in the light of the presentdisclosure, the drawings and the accompanying claims.

EXAMPLE 1

An improved dispensing device embracing the structural members actingtogether is manufactured as follows: first, a cylindrical shapedcontainer 2.33 cm long, 3.81 inside diameter and 4.67 mm outsidediameter, is injection molded at 180° C., at 77-84 kg/cm², from theelastomeric copolymer styrene-butadiene. Next, a mandrel is insertedinto the container, and this assembly placed into a two-piece cavitymold. Next, the mold charged with a mixture of 30 parts ofethyleneglycol monomethacrylate containing 0.12 of ethyleneglycoldimethacrylate, and 10 parts of 0.13% aqueous solution of sodiumdisulfate in aqueous ethanol. This mixture polymerizes at 30° C., andafter 20 minutes following equilibration to room temperature the mold isremoved.

Next, a solution of cellulose acetate in acetone, 15 wt% with an acetylcontent of 39.8%, is prepared and the mandrelsupported hydrogel coatedcontainers dipped into the solution 20 times for 1 minute per dip, withan intervening 15 minute drying period. Following this dipping, thesystems are dried at 60° C. for 15 days. This procedure applies a 0.65mm of the rate controlling wall onto the hydrogel lamina.

In operation, the above prepared system, when placed in a fluidenvironment, makes available improved controlled delivery of an agent.This is achieved by the wall acting in cooperation with the hydrogellamina. That is, the wall permits the passage of fluid at a controlledrate into the system, which fluid is imbibed and absorbed at acontrolled rate by the hydrogel. This double control provided by thesetwo lamina operating as a unit laminate leads to the controlledexpansion of the hydrogel lamina generating pressure that is appliedagainst the exterior surface of the container. The pressure causes thecontainer to be squeezed inwardly at a controlled rate andcorrespondingly dispense agent through the passageway at a controlledrate over time. Also, by preselecting the elastomeric material used forfabricating the container, an additional control is provided by thesystem.

EXAMPLE 2

The procedure of Example 1 is repeated with all conditions as set forth,except that the mold is filled with a cross-linked, swellable,hydrophilic polymer forming composition consisting essentially of 30parts by weight of hydroxyethyl methacrylate, 0.1 part by weight ofcross-linking agent ethylene dimethacrylate, and 8 parts by weight of a1-2% solution of sodium pyrosulfate. The mold is heated to about 30°-35°C. for about 15-25 minutes, and then for 5-10 minutes at about 100° C.In this example, the semipermeable polymer is cellulose acetate havingan acetyl content of 32% applied by using a Wurster air suspensionmachine.

EXAMPLE 3

The procedure of Example 1 is repeated with all conditions as describedexcept the wall coated onto the hydrogel is a microporous polymer withmicropores and micropaths therethrough that regulate fluid intake intothe system.

EXAMPLE 4

Representative of the structure of a therapeutic system made accordingto the invention that can be used for orally administering a drug is asfollows: (1) a rigid semipermeable lamina manufactured with an openinglaminated onto, (2) a lamina of poly(vinyl alcohol) cross-linked withglyoxal directly laminated onto (3) a container shaped and sized like a000 capsule with a single passageway for releasing drug and formed ofnatural rubber, with a drug formulation in the container comprising (4)tetracycline hydrochloride in polyethylene glycol 200.

Although the foregoing invention has been described in detail by way ofillustration of presently preferred embodiments and examples for thepurpose of clarity of understanding, it will be understood that certainchanges and modifications may be practiced without departing from thescope and spirit of the invention.

I claim:
 1. An agent dispensing device comprising:(a) a container forstoring a beneficial agent, said container formed of an elastomericpolymer that is changeable from an agent storing capacity to asubstantially emptied capacity over time; (b) a wall surrounding anddefining an internal space that houses the container, the wall formed ofa material selected from the group consisting of a semipermeable andmicroporous polymer that have selective fluid permeability and governsthe passage of fluid into the device at a controlled rate, maintains thephysical integrity of the device, and lets pressure be exerted againstit, thereby assuring that pressure generated in the device is appliedinwardly against the container; (c) a passageway communicating with thecontainer and the exterior of the device for dispensing agent from thedevice, said passageway having internal dimensions that assist ingoverning the rate of release of agent from the device; (d) a laminapositioned between the wall and the container in the device, said laminasurrounding the container and formed of a material that absorbs andretains an exterior fluid admitted into the device, and is capable ofchanging in size at a controlled rate in response to absorbed andretained fluid; and (e) wherein, when the device is in operation, fluidis admitted into the device at a rate controlled by the wall acting incooperation with the lamina that absorbs and retains the fluid, causingthe lamina to increase in size at a controlled rate and apply pressureagainst the container, which urges the container to squeeze inwardly ata corresponding rate and dispense agent through the passageway to theexterior of the device at a combined rate governed by the wall, lamina,container and the internal dimensions of the passageway.
 2. The agentdispensing device according to claim 1, wherein, the wall is formed ofmember selected from the group consisting of cellulose acylate,cellulose diacylate and cellulose triacylate.
 3. The agent dispensingdevice according to claim 1, wherein, the device is sized, shaped andadapted for use in the rectal passageway.
 4. The agent dispensing deviceaccording to claim 1, wherein, the lamina for absorbing and retainingfluid is a swellable, hydrophilic, cross-linked polymer.
 5. The agentdispensing device according to claim 1, wherein, the lamina forabsorbing and retaining fluid is formed of a member selected from thegroup consisting of lightly cross-linked poly(hydroxyalkylmethacrylate), poly(acrylamide), poly(methacrylamide),poly(N-vinyl-2-pyrrolidone), anionic and cationic hydrogels,poly(electrolytes) and protein polymers.
 6. The agent dispensing deviceaccording to claim 1, wherein, the container houses an agent that is adrug, which drug is present in solution, in semi-solid, or in athixotropic formulation.
 7. The agent dispensing device according toclaim 1, wherein, the container is formed of a member selected from thegroup consisting of natural rubber, gutta percha, cyclized rubber,silicone rubber isoprene rubber, butadiene rubber, styrene-butadienerubber, nitrile rubber, chloroprene rubber, ethylene-butylene rubber,and butyl rubber.
 8. The agent dispensing device according to claim 1,wherein, the container is formed with the passageway, and the lamina forabsorbing and retaining fluid is a swellable, hydrophilic polymer andhas a surface in contact with the container.
 9. The agent dispensingdevice according to claim 1, wherein, the container houses an agent thatis a drug, said drug a member selected from the group consisting oflocally and systemically acting drugs.
 10. The agent dispensing deviceaccording to claim 1, wherein, the device is sized, shaped and adaptedfor oral use and the dispensing of agent in the gastrointestinal tact.11. The agent dispensing device according to claim 1, wherein, thepassageway is connected to a conduit to transport dispensed agent to areceptor distant from the device.
 12. The agent dispensing deviceaccording to claim 1, wherein, the device is sized, shaped and adaptedfor dispensing agent in a vagina.
 13. The agent dispensing deviceaccording to claim 1, wherein, the device is sized, shaped and adaptedfor uses as an implant.